Current antivirals can control but not eliminate hepatitis-B-virus (HBV), because HBV establishes a stable nuclear cccDNA. Interferon-&#945; treatment can clear HBV but is limited by systemic side effects. IFN-&#945; is known to exert transcriptional, post-transcriptional and epigenetic antiviral effects on HBV. We study how interferon-&#945; can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-&#946;-receptor activation as a therapeutic alternative. Interferon-&#945; and lymphotoxin-&#946;-receptor activation up-regulated APOBEC3A and 3B cytidine-deaminases, respectively, in HBV-infected cells, primary hepatocytes and human liver-needle biopsies. HBV-core protein mediated the interaction with nuclear cccDNA resulting in cytidine-deamination, apurinic/apyrimidinic site formation and finally cccDNA degradation that prevented HBV-reactivation. On the other hand, genomic DNA was not affected. Our data indicate that cccDNA degradation is possible and can be induced without side-effects on the infected host cell. An important task will be testing of combinations of nucleos(t)ide analogues with novel anti-viral strategies (e.g. LT&#946;R agonists or adoptive T-cell therapy) to activate A3A or A3B to cure hepatitis B. Thus, inducing nuclear deaminases e.g., by lymphotoxin-&#946;-receptor activation allows development of new therapeutics that, combined with existing antivirals may cure hepatitis B.